Salvinorin A is a hallucinogenic neoclerodane diterpene isolated from the leaves of Salvia divinorum (Ortega 1982, Valdez 1984). Receptor binding studies revealed salvinorin A as a full agonist that has remarkable affinity as well as selectivity for the kappa opiate receptor (KOR) (Roth 2002). Salvinorin A is the most potent natural psychedelic agent thus far reported with a human dose ranging between 0.5-1 mg (Siebert 1994). This is the first reported example of an hallucinogen acting through the opiate receptor system and the first non-nitrogenous ligand that binds with high affinity/selectivity to a G protein-coupled receptor.
The KOR has been implicated in a wide variety of disease processes including: dementia, mood disorders, depression, schizophrenia, drug abuse, alcohol addiction, chronic pain conditions, seizure disorders, cognition enhancement, congestive heart failure, renal failure, augmentation of renal function, and diuresis. Thus, long-acting agonists or antagonists are very useful for a variety of disease states, and very useful for pharmacological studies of KOR activity. In particular, Salvinorin A-derived agonists which do not cross the blood brain barrier would be ideal to treat peripheral chronic pain conditions (osteo- and rheumatoid arthritis, degenerative joint disease, sciatica, and so on), congestive heart failure, renal failure, augmentation of renal function and diuresis, cancer, and HIV (Chao et al. 1998), while salvinorin A derived antagonists which cross the blood-brain barrier would be useful for treating mood disorders, schizophrenia, dementia, drug abuse, alcohol addiction, chronic central pain conditions, seizure disorders, HIV-related neuropsychiatric disorders, brain and spinal cord tumors and cognition enhancement.
The KOR system is a pharmaceutical curiosity due to its ability to modulate pain without causing euphoria, and hence addiction, through stimulation. In a recent report, it was shown that salvinorin A activates KOR's in subhuman primates and that the actions of salvinorin A are similar to those of other KOR agonists in vivo (Butleman et al. 2004). The hallucinogenic activity of salvinorin A also suggests the KOR plays some role in perception. Semi-synthetic modifications to the salvinorin skeleton may yield non-addictive opioid analgesics and/or KOR selective agonists or antagonists to treat the wide array of diseases associated with KOR.